Project Summary/Abstract Organisms with regenerative abilities have been informative models for uncovering natural mechanisms by which tissue damage activates stem or progenitor cells for injury repair. The timing, location, and extent of injuries are not predetermined, requiring the existence of mechanisms that instruct tissue restoration activities that perfectly counter the effects of damage. A key question to understand this process is how regenerative tissue redefines territories removed by injury, and it is hypothesized this is related to as-yet undiscovered systems that robustly regulate tissue proportionality across large length scales. To begin to address this question, it is essential to define the cell signaling systems that underlie regional identity and proportional growth. While regenerative tissues have been extensively probed for the roles of injury-induced signals and the involvement of stem or progenitor cells, much less is known about the molecular and developmental processes that enable the restoration of form after injury and its maintenance through adult growth. In the aims of this grant, this deficit is addressed by leveraging expertise in the planarian system, which uniquely allows for the study of signaling that regulates re-scaling of tissues through regeneration, to elucidate the regulatory and developmental mechanism that generates and restores tissue proportionality after injury. Uncovering fundamental mechanisms used by organisms to control tissue proportionality will provide foundational insights into understanding diseases of growth misregulation, the nature of proportional growth, and the control of stem cells for tissue regeneration.